As the COVID-19 pandemic drags into its second year, there is hope on the horizon, in the form of SARS-CoV-2 vaccines which promise disease suppression and a return to pre-pandemic normalcy. In this study we critically examine the basis for that hope, using an epidemiological modeling framework to establish the link between vaccine characteristics and effectiveness in bringing an end to this unprecedented public health crisis. Our findings suggest that a return to pre-pandemic social and economic conditions without fully suppressing SARS-CoV-2 will lead to extensive viral spread, resulting in a high disease burden even in the presence of vaccines that reduce risk of infection and mortality. Our modeling points to the feasibility of complete SARS-CoV-2 suppression with high population-level compliance and vaccines that are highly effective at reducing SARS-CoV-2 infection. Notably, vaccine-mediated reduction of transmission is critical for viral suppression, and in order for partially-effective vaccines to play a positive role in SARS-CoV-2 suppression, complementary biomedical interventions and public health measures must be deployed simultaneously.
Abstract The ongoing COVID-19 pandemic has created an urgent need for antiviral treatments that can be deployed rapidly. Drug repurposing represents a promising means of achieving this objective, but repurposing efforts are often unsuccessful. A common hurdle to effective drug repurposing is a failure to achieve a sufficient therapeutic window in the new indication. A clear example is the use of ivermectin in COVID-19, where the approved dose (administered orally) fails to achieve therapeutic concentrations in the lungs. Our proposed solution to the problem of ineffective drug repurposing for COVID-19 antivirals is two-fold: to broaden the therapeutic window by reformulating therapeutics for the pulmonary route, and to select drug repurposing candidates based on their model-predicted therapeutic index for inhalation. In this article, we propose a two-stage model-driven screening and validation process for selecting inhaled antiviral drug repurposing candidates. While we have applied this approach in the specific context of COVID-19, this in vitro-in vivo translational methodology is also broadly applicable to repurposing drugs for diseases of the lower respiratory tract.
Simian virus 5 (SV5) is a member of the paramyxovirus family, which includes emerging viruses such as Hendra virus and Nipah virus as well as many important human and animal pathogens that have been known for years. SV5 encodes eight known viral proteins, including a small hydrophobic integral membrane protein (SH) of 44 amino acids. SV5 without the SH gene (rSV5deltaSH) is viable, and growth of rSV5deltaSH in tissue culture cells and viral protein and mRNA production in rSV5deltaSH-infected cells are indistinguishable from those of the wild-type SV5 virus. However, rSV5deltaSH causes increased cytopathic effect (CPE) and apoptosis in MDBK cells and is attenuated in vivo, suggesting the SH protein plays an important role in SV5 pathogenesis. How rSV5deltaSH induces apoptosis in infected cells has been examined in this report. Tumor necrosis factor alpha (TNF-alpha), a proinflammatory cytokine, was detected in culture media of rSV5deltaSH-infected cells. Apoptosis induced by rSV5deltaSH was inhibited by neutralizing antibodies against TNF-alpha and TNF-alpha receptor 1 (TNF-R1), suggesting that TNF-alpha played an essential role in rSV5deltaSH-induced apoptosis in a TNF-R1-dependent manner. Examination of important proteins in the TNF-alpha signaling pathway showed that p65, a major NF-kappaB subunit whose activation can lead to transcription of TNF-alpha, was first translocated to the nucleus and was capable of binding to DNA and then was targeted for degradation in rSV5deltaSH-infected cells while expression levels of TNF-R1 remained relatively constant. Thus, rSV5deltaSH induced cell death by activating TNF-alpha expression, possibly through activation of the NF-kappaB subunit p65 and then targeting p65 for degradation, leading to apoptosis.
In 2012, an unprecedented large-scale outbreak of disease in pigs in China caused great economic losses to the swine industry. Isolates from pseudorabies virus epidemics in swine herds were characterized. Evidence confirmed that the pathogenic pseudorabies virus was the etiologic agent of this epidemic.
OBJECTIVES: Combination therapies hold great promise in the management of adversarial diseases such as cancer and infectious diseases, but they are limited in their potential by drug tolerability. A systematic evaluation of the impact of dose scheduling on the therapeutic window of combination therapies can provide valuable insights into their design. Here we present a simplified quantitative systems pharmacology framework for the assessment of schedule dependence for combination therapies that can provide a basis for the rigorous assessment of such combinations, focused on cancer as a motivating example.METHODS: We used a simplified tumor dynamics model with subpopulations of cancer cells being resistant to none, one, two or three drugs in all possible combinations. Tumor dynamics were simulated based on an exponential growth model that suffered growth penalties dependent on the drug concentrations [1]. To determine the effect of a three-drug combination on tumor growth, we simulated the concentrations of three drugs using a one-compartment pharmacokinetic model. Final tumor volume and peak toxicity were used to compare the effectiveness of various dosing strategies and interaction combinations. For the toxicity constraint, we simulated a neutropenia-like toxicity for all three drugs (which we have previously shown to be proportional to the peak moving average of drug concentrations over 18 days [2]).RESULTS: Our model suggests that the impact of drug synergy and antagonism are strongest when drugs are dosed synchronously. In particular, simultaneously dosing three drugs with overlapping toxicities is vulnerable to the extent of (undesirable) synergy in their toxicities. The time-sensitivity— that is, the magnitude of the changes in efficacy associated with small changes in schedule— varies with phase offset of drug dosing. On the flip side, dosing completely asynchronously in our model provides the greater opportunity for the emergence of resistant populations. A potential compromise is the simultaneous dosing of two of the three drugs, which results in an intermediate toxicity. CONCLUSIONS: Our work provides a generalized framework for the design of three-drug combinations that can readily be extended to the optimization of specific drug combinations. At the same time, the model provides some fundamental strategic insights about multi-drug combinations. First, the degree of synergy for efficacy and toxicity play a strong role in feasibility. Second, the toxicity constraint will limit the feasibility of effective disease control for many multidrug combinations. Third, drugs that are strongly synergistic in their efficacy may be highly time-sensitive in their dosing, which can be impractical in a clinical setting. Finally, striking a balance between efficacy and toxicity may be easier to achieve for drugs that have independent effect on efficacy (additive), but have non-overlapping toxicity profiles. Citations: 1. Bottino D, Chakravarty A. (2016) Modeling Tumor Growth in Animals and Humans: An Evolutionary Approach. In: Bonate P., Howard D. (eds) Pharmacokinetics in Drug Development. Springer, Cham. https://doi.org/10.1007/978-3-319-39053-6_11.2. Patel M, Palani S, Chakravarty A, Yang J, Shyu WC, Mettetal JT. Dose schedule optimization and the pharmacokinetic driver of neutropenia. PLoS One. 2014 Oct 31;9(10):e109892. doi: 10.1371/journal.pone.0109892. PMID: 25360756; PMCID: PMC4215876.
At 18,954 nucleotides, the J paramyxovirus (JPV) genome is one of the largest in the family Paramyxoviridae, consisting of eight genes in the order 3'-N-P/V/C-M-F-SH-TM-G-L-5'. To study the function of novel paramyxovirus genes in JPV, a plasmid containing a full-length cDNA clone of the genome of JPV was constructed. In this study, the function of the small hydrophobic (SH) protein of JPV was examined by generating a recombinant JPV lacking the coding sequence of the SH protein (rJPVΔSH). rJPVΔSH was viable and had no growth defect in tissue culture cells. However, more tumor necrosis factor alpha (TNF-α) was produced during rJPVΔSH infection, suggesting that SH plays a role in inhibiting TNF-α production. rJPVΔSH induced more apoptosis in tissue culture cells than rJPV. Virus-induced apoptosis was inhibited by neutralizing antibody against TNF-α, suggesting that TNF-α contributes to JPV-induced apoptosis in vitro. The expression of JPV SH protein inhibited TNF-α-induced NF-κB activation in a reporter gene assay, suggesting that JPV SH protein can inhibit TNF-α signaling in vitro. Furthermore, infection of mice with rJPVΔSH induced more TNF-α expression, indicating that SH plays a role in blocking TNF-α expression in vivo.
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